All amino acids other than glycine have two optical isomers, referred to as D-type and L-type. The L-amino acids are used in protein synthesis in organisms, and the amino acids contained in proteins are mostly L-amino acids. On the other hand, although D-amino acids are contained in some of the biologically active peptides of lower forms of life, such D-amino acid-containing peptides are often biosynthesized during a process of post-translation modification. That is to say, amino acids, which constitute proteins and peptides, are predominantly L-amino acids, and D-amino acids are an exceptional presence.
D-amino acids are structural constituents of peptide glycans of the cell walls of bacteria. Furthermore, it has been reported that free D-amino acids that do not constitute the peptides are present in lower animals, such as aquatic animals and insects. However, there was a time when it was believed that the amino acids present in higher animals are of the L-type, and that the D-type was present only in trace quantities (Non-Patent Document 1),    [Non-Patent Document 1] Corrigan J. J., Science 164:142-149 (1969).
However, the presence, and the role thereof, of D-amino acids in mammals, including humans, is only just becoming clear in recent years, due to advances in analytical methods such as optical resolution methods (Non-Patent Document 2). In regard to D-aspartate, as a result of double staining methods using an anti-D-aspartate antibody, or the like, it became clear that it is localized in the prolactin producing cells in rat pituitary glands. Furthermore, administration of D-aspartate to cells of a rat pituitary gland-derived cell line that produces and secretes prolactin increases dose-dependently the prolactin secretion. Therefore, it is considered that D-aspartate controls the secretion of prolactin in prolactin producing cells (Non-Patent Document 3).    [Non-Patent Document 2] Hamase K, Morikawa A, and Zaitsu K., J Chromatogr B 781: 73-91 (2002).    [Non-Patent Document 3] D'Aniello A et al., FASEB J 14: 699-714 (2000).
On the other hand, it has been reported that in addition to higher concentrations of D-aspartate constantly being detected in the veins of rat testes compared to in other veinous blood, the synthesis and secretion of testosterone is dose-dependently promoted by providing D-aspartate to Leydig cells isolated and purified from rat testes (Non-Patent Document 4).    [Non-Patent Document 4] Nagata Y et al., FEBS Lett. 444:160-164 (1999).
It has been reported that D-serine selectively stimulates the glycine binding site of the NMDA receptor, which has been supposed to be associated with schizophrenia, and that neural transmission can be promoted by enhancing the function of glutamate via this receptor (Non-Patent Document 5). It has been reported that schizophrenia is actually improved by the administration of D-serine, and that schizophrenic patients have a lower D-serine concentration in the blood serum compared to healthy individuals.    [Non-Patent Document 5] Nishikawa T, Biol. Pharm. Bull. 28: 1561-1565 (2005).
With regard to the skin science, there is a report in which D-aspartate is present in tissue in which the turnover of proteins does not occur readily, such as in the eye lens (Non-Patent Document 6). Furthermore there is a report that suggests that UV exposure has a strong relationship with D-aspartate formation in the elastic fiber of the skin, since D-aspartate is contained in the elastic fiber of sunburnt skin of elderly subjects but is not contained in the elastic fiber of skin that is not sunburnt (Non-Patent Document 7).    [Non-Patent Document 6] Fujii N et al., Biol. Pharm. Bull, 28: 1585-1589 (2005).    [Non-Patent Document 7] Fujii N. et al., Biochem. Biophys. Res. Commun. 294, 1047-1051 (2002).
However, a large obstacle in exploring the presence and the role of D-amino acids in the mammal, including the human, is that D-amino acids are rapidly degraded. During the degradation of D-amino acids, firstly, the D-amino acid is oxidatively deaminated by a D-amino acid oxidase (EC 1.4.3.3, hereunder referred to as “DAO enzyme”), and is converted to the corresponding α (alpha)-keto acid. Thereafter, the α (alpha)-keto acid is converted to the corresponding L-amino acid by a transaminase. The DAO enzyme is an enzyme that specifically oxidizes D-amino acids, and is expressed in the kidneys, and other organs (Non-Patent Document 8).    [Non-Patent Document 8] Hamase K., Konno R., Morikawa A. and Zaitsu K., Biol. Pharm. Bull, 28: 1578-1584 (2005).
Although the DAO enzyme is encoded by the Dao1 gene of the fifth chromosome in mouse, the missense mutant of this gene was reported in ddY mouse (Non-Patent Document 9). In this mutant gene allele (Daoc or DaoG181R), the Gly residue in position number 181 is substituted by an Arg residue, resulting in a protein that has lost its enzyme activity. Accordingly, the phenotype of the DAO enzyme inactivation is recessively inherited. In an individual of a recessive homozygote (hereunder referred to as a “DAO enzyme deficient mouse”), the blood serum concentration of D-alanine and D-serine rises between 5 to 8 times, and exhibits ataxia and stereotypic behavior (Non-Patent Document 10). There are no reports regarding mating experiments between a DAO enzyme deficient mouse and other disease model mice,    [Non-Patent Document 9] Konno R. and Yasumura Y. Genetics 103: 277-285 (1983).    [Non-Patent Document 10] Hashimoto A., Yoshikawa M., Niwa A. and Konno R., Brain Res. 1033:210-215 (2005).